Comprehensive Review on the Use of Oral Cholera Vaccine (OCV) in Ethiopia: 2019 to 2023

Abstract Background Cholera outbreaks in Ethiopia necessitate frequent mass oral cholera vaccine (OCV) campaigns. Despite this, there is a notable absence of a comprehensive summary of these campaigns. Understanding national OCV vaccination history is essential to design appropriate and effective cholera control strategies. Here, we aimed to retrospectively review all OCV vaccination campaigns conducted across Ethiopia between 2019 and 2023. Methods The OCV request records from 2019 to October 2023 and vaccination campaign reports for the period from 2019 to December 2023 were retrospectively accessed from the Ethiopia Public Health Institute (EPHI) database. Descriptive analysis was conducted using the retrospective data collected. Results From 2019 to October 2023, Ethiopian government requested 32 044 576 OCV doses (31 899 576 doses to global stockpile; 145 000 doses to outside of stockpile). Around 66.3% of requested doses were approved; of which 90.4% were received. Fifteen OCV campaigns (12 reactive and 3 pre-emptive) were conducted, including five two-dose campaigns with varying dose intervals and single-dose campaigns partially in 2019 and entirely in 2021, 2022 and 2023. Overall vaccine administrative coverage was high; except for Tigray region (41.8% in the 1st round; 2nd round didn't occur). The vaccine administrative coverage records were documented, but no OCV coverage survey data was available. Conclusions This study represents the first comprehensive review of OCV campaigns in Ethiopia spanning the last five years. Its findings offer valuable insights into informing future cholera control strategies, underscoring the importance of monitoring and evaluation despite resource constraints. Addressing the limitations in coverage survey data availability is crucial for enhancing the efficacy of future campaigns.


INTRODUCTION
Vaccination is a feasible rapid intervention to prevent the emergence of cholera and contain further spread during outbreaks [1].Among three World Health Organization (WHO)-prequalified oral cholera vaccines (OCVs) (Dukoral®, Shanchol ™ , and Euvichol-Plus®), Shanchol ™ and Euvichol-Plus® have been supplied to the global OCV stockpile and used for mass vaccination campaigns [2].A Gavi supported global stockpile of OCV was established in 2013 to support the OCV use in outbreak responses (through the International Coordinating Group [ICG] approval process) [1].In 2017, the "Ending Cholera: A Global Roadmap to 2030" was launched and the use of OCV was expanded to include preventive campaigns with approval of requests initially made by the WHO Global Task Force on Cholera Control (GTFCC) [3].Currently, access to OCV for preventive campaigns requires a multi-year plan and application through Gavi [4].Since the 2019 cholera outbreaks, the Ethiopian government has submitted several official requests to the ICG for reactive and preventive use of OCV doses from the global stockpile [5] and an additional request was made to the government of the Republic of Korea bilaterally in response to the mass cholera outbreaks [6].In parallel, the "Multi-sectoral Cholera Elimination Plan, Ethiopia 2022-2028' was developed by the Ethiopian government, which has been endorsed nationally and announced at the 75th World Health Assembly in 2022; encompassing the potential future use of OCVs based on the mapping of cholera "hotspots" [7].

S U P P L E M E N T A R T I C L E
In 2019, GTFCC OCV Working Group published a review paper on the global OCV use for 5 years, since the establishment of stockpile in 2013, to draw lessons from global OCV deployments and related campaigns [8].The review paper demonstrated that many countries were using OCVs for both outbreak response and endemic cholera prevention with high coverage in general [8].However, some campaigns showed relatively lower coverage in adult males and some decreased coverage was observed during the second round of vaccination [8].In addition, there was a delay between onset of outbreak and implementation of vaccination and/or between the first round and second round [8].According to this report, Ethiopia is one of the countries that received more than 1 million doses of OCV from the global stockpile between 2013 and 2018 [8].Since 2019, however, the number of received doses has significantly increased to approximately 18 million doses [5].To trace and understand this increased OCV deployment in Ethiopia, documenting and reviewing OCV campaigns conducted in Ethiopia would be important.The GTFCC cholera research agenda suggests evidence-generation on OCV use, including the community level duration of protection per dosing schedule, the impact of OCV vaccination timing on outbreak prevention and control, and potential delivery strategies to optimize OCV coverage [9].A comprehensive review of past use of OCVs in the country could provide the groundwork for future research to address these gaps and policies.Moreover, analyzing such vaccination history data including coverage will also provide an opportunity to identify barriers to uptake and characterize acceptance towards cholera vaccines [10,11], and lessons learned regarding feasibility and efficiency of strategies, and ultimately these impacts could improve future campaigns.
Here we aimed to conduct a comprehensive retrospective review of all OCV vaccination campaigns conducted in Ethiopia from 2019 to 2023.The GTFCC monitoring and reporting guidelines on the use of OCV recommends the tracking of: OCV administrative coverage per vaccination campaigns; proportion of hotspots targeted by the vaccination plans; and the proportion of doses used in campaigns to respond to an outbreak compared to doses administered during preventive campaigns [12].Our review focused on the OCV doses requested to the ICG by vaccination type, approved, and delivered; OCV dose numbers and dose intervals applied in each campaign and rolled-out per region, zone, and woreda; OCV vaccination periods per campaign; OCV coverage rates per region, zone, and woreda in Ethiopia; and sex and age-stratified information on the OCV vaccinated populations.

Dataset Description
The OCV request records from 2019 to October 2023 and vaccination campaign reports for the period from 2019 to December 2023 were retrospectively accessed from the Ethiopia Public Health Institute (EPHI) database.The data prior to 2019 were scattered and challenging to obtain and therefore not included in this analysis.Ethiopia officially has 4 levels of administrative division: Region, Zone, Woreda, and Kebele in descending size order.Ethiopia uses an excel-based and paper-based data collection method to document all OCV vaccination-related data at kebele (ward)-and woreda (district)-level, and subsequently compiled into a national database.
Regional level data are collected using the Open Data Kit (ODK) system.This data set included: date and number of OCV doses requested, approved, and received; OCV vaccination campaigns conducted per region, zone, woreda with planned and actual number of doses administered; OCV vaccination administrative coverage based on actual doses administered and number of population targeted per vaccination target areas (based on the latest administrative census); and sex-and age-stratified data on populations administered with cholera vaccines.Because not all kebeles in targeted woredas were always selected for vaccination, total population number per woreda and population of vaccination targeted kebeles were separately reported in the paper.

Data Analysis
The request numbers refer to each OCV request made by the Ethiopian government to the ICG, according to the EPHI records.For non-stockpile requests, a discernible request number was given in our analysis.Total population of woredas represent population in the year when OCV vaccination campaigns were conducted.In most past OCV campaigns, the target population was the population in kebeles planned for vaccine administration, excluding infants under 1 year old.The OCV administrative coverage was calculated based on the actual number of people vaccinated (numerator) out of the OCV target populations (denominator) in each round of vaccination per region, zone, and woreda levels in Ethiopia.

OCV Doses Requested, Approved, Received, and Used in Ethiopia
From 2019 until October 2023, a total of 32 044 576 OCV doses were requested by the Ethiopian government with 31 899 576 doses (11 requests: A1-A11) to the ICG and 1 request for 145 000 doses through the government of the Republic of Korea.The OCV doses (202 491) used in a preemptive vaccination in May 2022 [13] 1, Figure 1).The request A6, which was almost immediately after the ICG changed to a single dose recommendation for reactive campaigns in October 2022, shows only 4.3% (86 910/2 000 466) of the requested OCV doses were approved and received in Ethiopia for this outbreak response due to extreme shortage of vaccine in the global stockpile.
Generally, all approved doses were delivered to Ethiopia, but the request A4 for reactive vaccination campaign in Tigray region was exceptional (4 017 218 requested and approved; 2 008 650 delivered).When a campaign is designed for 2 rounds, approved OCV doses are usually shipped in a separate batch per round according to the campaign schedule, and OCV doses for second round are delivered after a technical report from first round is submitted to the ICG.In the case of Tigray campaign, the first round's technical report concluded that the second round could not be implemented due to insecurity in the region and the second-round doses were not sent although the doses for 2 rounds had been approved.Of the total 31 899 576 doses (requests A1-A11) requested, 21 148 800 doses were approved, of which 19 113 386 doses were delivered to Ethiopia and 17 488 992 doses were administered.Based on the available records, 2033 doses were not used due to vaccine vial monitor (VVM) change signifying lack of integrity of the cold chain which occurred in the hard-to-reach areas under conflict.76 257 unused doses were returned to the Ethiopian Pharmaceuticals Supply Agency (EPSA) for cold chain storage, to be used for future reactive vaccination, such as campaigns conducted in Afar and Amhara region in 2022 (Table 2).Among the gap of 1 546 104 doses between delivered and administered, 1 167 876 doses could not be used in Tigray campaign as planned and have not been retrieved to EPSA yet.The remaining gap of 378 228 doses is attributed to remaining doses from prior campaigns but marked as "not applicable" in the database or some damaged vials which were not described in Table 1.

OCV Vaccination Dose Intervals and Coverage per Region, Zone, and Woreda in Ethiopia
Based on the OCV doses received from requests A1-A11, 17 488 992 people were vaccinated with either a single dose (SD) or 2-doses (2D) of OCV with different dosing schedules (Table 2, Supplementary Table 1, Figure 2).The OCV doses from request A1 were administered as 2D with 24-week dose interval in Oromia region with 97.5% administrative coverage in first round and 95.9% in second round, but SD strategy was used in other cholera vulnerable regions due to the shortage of the vaccine.OCV doses were requested for pre-emptive vaccination in Tigray region, a site of ongoing conflict.Tigray campaign was    2).Reactive vaccination campaigns implemented between 2020 and 2021 (request A2, A3, A5) used recommended 2D regimen but dose intervals were more than 2 weeks.In April and May 2022, OCV vaccinations were carried out in Afar and Amhara regions to respond to the outbreak in each region.Leftover doses from other OCV vaccination campaigns conducted prior to April 2022, which have been stored at EPSA, were used for SD strategy to cover more people (Table 2).Six reactive vaccinations in 2023 administered SD reflecting the ICG recommendation in global OCV shortage setting.

Sex-and Age-Stratified OCV Vaccination in Ethiopia
The sex-and age-stratified data on the OCV vaccinated populations for each vaccination campaign from 2019 to 2023 were described (Table 3, Supplementary Table 2, and Figure 3).There was no sex and age data for the campaign conducted in Southern Nations, Nationalities, and Peoples' Region (SNNPR) and Somali regions in 2019 through bilateral request and Tigray campaign (request A4).Overall, local populations aged 15 years and older received the largest number of doses of OCV regardless of SD or 2D administration (Table 3), both first (Figure 3A) and second round (Figure 3C); followed by children aged between 5-14 years and 1-4 years.An exception was in the A1 request related OCV use during the second round of vaccination campaign, where children aged 5-14 years 610) were vaccinated slightly more than those aged 15 years and older (109 626) (Table 3 and Supplementary Table 2).The proportion of male and female populations vaccinated with OCV was similar regardless of dosing schedules or campaign types (Figure 3B and Figure 3D).

DISCUSSION
Overall, 15 OCV mass vaccination campaigns were conducted in Ethiopia from 2019 to 2023.11 campaigns (9 reactive and 2 preemptive campaigns) used OCV doses received through requests made to the global stockpile of OCVs and 2 reactive campaigns in Afar and Amhara region in 2022 used some remaining doses from prior campaigns.OCV doses obtained from outside of global stockpile (a bilateral channel and a research project) were used for 1 reactive campaign and 1 preemptive vaccination, respectively.This preemptive vaccination campaign result under the research project is presented in this CID Supplement [13].
Most of the OCV requests were deployed in response to cholera outbreaks, and dose intervals were more than standard 2 weeks in the case of 2-rounds campaigns.Regardless of dose regimen, all areas targeted showed high administrative coverage except for Tigray region, but formal post-campaign coverage surveys have not been conducted in Ethiopia.Generally, population aged 15  During the vaccination campaign implemented in 2019, the Ethiopian government used a SD strategy to cover broader outbreak area due to shortage of the vaccine, except parts of Oromia region where 2D vaccination was rolled-out considering the severity of outbreak in the region [14].The ICG SD recommendation was announced in October 2022 in response to large scale global cholera epidemics and the shortage in global OCV stockpile [15].Debates on the effectiveness and impact of SD are ongoing with limited research available thus far.However, some modeling studies demonstrate a speedy vaccination with SD of OCV under a limited vaccine supply may avert more cholera cases and deaths in outbreak setting compared to a standard 2D regimen [16,17].Nonetheless, the effectiveness, duration of protection and impact of SD OCV intervention may differ in populations living in different environments with varying degrees of cholera endemicity [18]; as well as between age-groups as children under 5 years may receive limited benefit from an SD [19,20].All mass OCV vaccination campaigns conducted in Ethiopia from 2022 used SD strategy (except for the campaign under the ECCP project in May 2022), but no follow-up studies have been performed to investigate SD effectiveness or to explore how long protection would last or optimal timing of catch-up second dose vaccination.
In addition to dose regimen, optimal and feasible dosing schedule is another point to be considered for effective vaccination.The standard dose interval of OCV is 2 weeks [21], but it is not feasible to strictly follow in most emergency settings.Among 5 OCV vaccination campaigns with 2D regimen conducted in Ethiopia from 2019, only 1 vaccination campaign implemented in Shashemene area in May 2022 (under the ECCP research project) adopted the standard 14-day dose interval [13].The remaining 2D vaccination campaigns showed varying dose intervals from 9 weeks to 24 weeks.Similar to the SD, there are limited studies on OCV dosing schedules.Several studies have explored immunogenicity of alternative dose intervals and found generally comparable immune responses at intervals of 1 or 6 months [22,23].A SD strategy may be able to reduce the urgent risk of cholera infection in an ongoing outbreak for the short term; but an extended interval dose is recommended to make     protection robust even with delays in the second dose [20,23,24].Nevertheless, this may not be an easy task in the real-world setting.A study conducted in Lusaka, Zambia, suggested the long delay between doses can make people miss an opportunity to get full 2-doses OCV because of population movement [25].However, further operational research on a longer dosing interval is warranted to answer questions on the effectiveness and impact in real-world settings.One of the priorities in the GTFCC cholera research agenda is finding vaccination delivery strategies for "hard-to-reach populations" such as internally displaced people (IDP) [9].This facet is also important to consider because areas of insecurity may be at risk for cholera outbreaks and difficult to provide immunization [26][27][28].In Ethiopia, the government conducted campaigns to prevent cholera outbreaks amid the conflict region in Tigray regional state in 2021 [29], targeting populations living in the conflict affected communities and IDP.However, significantly lower vaccination administrative coverage (41.8% in the first round; and second round did not occur) was reported from all woredas in Tigray region during this period as a result of the challenging operational situation on the ground.For instance, barriers to sufficient community engagement and sensitization, limited access to health centers and posts, and management of overall mass vaccination campaigns with proper record keeping and documentations.EPHI uses a mixed vaccination campaign strategy (door-todoor; fixed posts), and campaigns are integrated with other response pillars including surveillance and water, sanitation, and hygiene interventions.Yet it underscores how difficult it can be to implement vaccination effectively in a conflict setting and may infer necessity of identifying and building logistical and operational strategy to equitably administer OCVs to hard-to-reach and vulnerable populations [30].
No post-campaign coverage surveys have been conducted in Ethiopia due to the constraints of manpower and time in the face of the upsurge in outbreaks.Coverage surveys are important to understand the actual coverage estimates of SD or 2D which can differ from administrative coverage [31].Indeed, one coverage survey data was available from 2D pre-emptive vaccination in 2022, implemented under ECCP project.The 2D coverage estimate was approximately 80% (78% in Shashemene Town; 83% in Shashemene Woreda) whereas administrative coverages of first and second round reached nearly 100% [13].Coverage surveys including age and sex demographics provide important information regarding vaccine acceptance as well as reasons for non-vaccination which are important for improving future campaigns [32][33][34][35][36].In addition, OCV is known to provide indirect or herd protection enhancing the overall impact, but which can vary with coverage rate [37,38].With the data available currently in Ethiopia, it is difficult to know actual coverage per dose or have data to inform improvement in future campaigns.Fortunately, as of November 2023, EPHI is conducting coverage studies in Afar, Oromia, South and Central Ethiopia regions to collect comprehensive coverage data using a pre-developed protocol.The coverage survey will be implemented within 2 weeks of campaign end date for every future OCV campaign.

CONCLUSION
To our knowledge, this is the first comprehensive review paper documenting all OCV requests made by the Ethiopian government from 2019 to October 2023 and mass vaccination campaigns implemented across the country in the last 5 years.Five full approvals and six partial approvals were made by the ICG, and 66.3% of OCV requests were approved.Of the approved OCV doses, 90.4% were delivered to Ethiopia.In spite of many challenges, the Ethiopian government was able to conduct numerous campaigns both reactive and preemptive in many settings, achieving high administrative coverage.Because of the inherent inaccuracies in administrative coverage data, coverage surveys should be carried out in future campaigns.A comprehensive review of past OCV vaccinations implemented in Ethiopia not only supports better planning of effective national OCV vaccination in the future but also generates the framework for future research areas.

S20•
CID 2024:79 (15 July) • Edosa M. and Jeon Y. et al Abbreviations: ECCP, Ethiopia Cholera Control and Prevention; n.a, not applicable; OCV, oral cholera vaccine; VVM, Vaccine Vial Monitor.The bold values refer to the total or subtotal amount.a Request number refers to each OCV request made by the Ethiopian government.b Request Type refers to a preemptive/preventive or reactive campaign per the Ethiopian government's OCV request dossiers.

Figure 1 .
Figure 1.OCV doses made available in Ethiopia from 2019 to October 2023.The figure shows OCV doses requested, approved, and received in Ethiopia from 2019 to October 2023, and doses used in last 5 years."Request number" refers to each OCV request made by the Ethiopian government to the ICG (A1-A11) and non-stockpile requests (Bilateral, ECCP)."Bilateral" represents the Ethiopian government's bilateral request to the government of the Republic of Korea for OCV doses for cholera outbreak control in 2019."ECCP" represents "Ethiopia Cholera Control and Prevention" project."Afar" and "Amhara" represent preventive vaccination campaigns conducted in Afar and Amhara region, respectively using remaining OCV doses from other vaccination campaigns.Abbreviation: OCV, oral cholera vaccine.
setting of insecurity or armed conflict, resulting in the lowest OCV administrative coverage across all vaccination campaigns conducted in Ethiopia from 2019 to December 2023 (Table Abbreviations: n.a, not applicable; OCV, oral cholera vaccine; SD, single dose; SNNPR: Southern Nations, Nationalities, and Peoples' Region; 2D, 2 doses; wks, weeks.The bold values refer to the total or subtotal amount.a Request number refers to each OCV request made by the Ethiopian government.b In first round.OCV target population is the population of OCV vaccination targeted kebeles in each woreda excluding infants (ie, < 1 y).

Figure 2 .
Figure 2. Map of OCV vaccination campaign areas.The map comprehensively shows woredas where OCV vaccination campaigns have been conducted from 2019 to 2023.Number of vaccination rounds conducted in each woreda is represented as either R1 or R2.Abbreviations: ECCP, Ethiopia Cholera Control and Prevention; OCV, oral cholera vaccine.
Comprehensive Review on the Use of Oral Cholera Vaccine (OCV) in Ethiopia: 2019 to 2023 • CID 2024:79 (15 July) • S27 Abbreviations: n.a, not applicable; OCV, oral cholera vaccine; SNNPR: Southern Nations, Nationalities, and Peoples' Region; y: years.The bold values refer to the total or subtotal amount.a Request number refers to each OCV request made by the Ethiopian government.b In first round.

Figure 3 .
Figure 3. Age group and sex-stratified OCV vaccinated populations from 2019 to 2023.Panels A-D show age groups and sex of OCV vaccinated populations in each vaccination campaigns."Request number" refers to each OCV request made by the Ethiopian government to the ICG (A1-A11) and non-stockpile requests (Bilateral, ECCP)."Bilateral" represents the Ethiopian government's bilateral request to the government of the Republic of Korea for OCV doses for cholera outbreak control in 2019."ECCP" represents "Ethiopia Cholera Control and Prevention" project."Afar" and "Amhara" represent preventive vaccination campaigns conducted in Afar and Amhara region respectively using remaining OCV doses from other vaccination campaigns.Age and sex stratified data of OCV vaccinated populations from Bilateral and A4 were not available.Afar, Amhara, and A6-A11 administered single dose (SD) strategy; there was no second round information.Panels A and B exhibit age group and sex stratifications of populations vaccinated respectively in the 1st round; Panels C and D exhibit age group and sex stratifications of populations vaccinated respectively in the 2nd round.Abbreviation: OCV, oral cholera vaccine.